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    3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide Derivatives: Design, Synthesis and Neuroprotectivity Potential Against 6-OHDA Induced Neurotoxicity Model
    (Galenos Publ House, 2025) Tarikogullari Dogan, Ayse Hande; Saylam, Merve; Yilmaz, Sinem; Parlar, Sulunay; Ballar, Petek; Alptuzun, Vildan
    Objectives: Excessive amounts of neuroapoptosis are the underlying cause of neurodegenerative diseases. Bax is a pro-apoptotic member of the B-cell lymphoma-2 family that activates caspases which are the members of the cysteine protease family that play a significant role in the initiation and execution phases of apoptosis. The aim of this study was to design and synthesize a group of N-propananilide derivatives bearing pyrazole or 1,2,4-triazole ring were designed and synthesized to analyze the neuroprotectivity potential against 6-hydroxy-dopamine (6-OHDA). Four compounds possessed protectivity at lower doses were subjected to further studies on caspase-3 and Bax pathway. Materials and Methods: Designed compounds were synthesized by reacting 1H-pyrazole or 1H-1,2,4-triazole with propananilide intermediates in Dimethylformamide. The neuroprotective activity of the title compounds was analyzed against 6-OHDA-6-OHDA-induced neurotoxicity model. Then, caspase-3 and Bax levels were determined for the selected compounds by Western blot study. Results: All twelve 3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide derivatives possessed neuroprotectivity against the 6-OHDA-induced neurotoxicity model (p <= 0.05, **p <= 0.001, ***p <= 0.005). Compounds 7, 10, 11, and 12 were found to be more active at lower doses. They were subjected to further studies and the results revealed that their protecting activity arose from the decreasing levels of Bax, one of the pro-apoptotic proteins, Conclusion: All designed and synthesized derivatives possessed neuroprotectivity against 6-OHDA-induced neurotoxicity in the SH-SY5Y cell line and compounds 7, 10, 11, and 12 revealed that their neuroprotectivity originated from the decreasing Bax expression levels and caspase-3 activation.
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    A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity-induced PARylation in SIN1-mediated neurotoxicity
    (John Wiley and Sons Inc, 2021) Yilmaz, Sinem; Alkan, Tolgaç; Ballar Kirmizibayrak, Petek
    Increased levels of reactive oxygen and nitrogen species play an important role in the development and progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The overproduction of these highly reactive chemical species leads to DNA damage and subsequent activation of the poly(ADP-ribose)polymerase (PARP) enzyme. Several studies have demonstrated the potential use of PARP inhibitors for neuroprotection. We previously reported that the dual Src/Abl kinase inhibitor bosutinib (BOS) decreases PARP activity and acts as a chemosensitizer in cancer cells. In this study, we evaluated the neuroprotective potential of BOS with respect to its inhibitory effect on cellular poly(ADP-ribos)ylation (PARylation) using a 3-morpholinosydnonimine (SIN1)-mediated cellular toxicity model. Our data suggest that pretreatment with BOS, especially at lower doses, significantly decreased the level of SIN1-induced cellular PARylation. This regulation pattern of PARylation was found to be associated with the protective effect of BOS against SIN1 on the viability of retinoic acid-differentiated SH-SY5Y cells. Furthermore, while PARP-1 expression was decreased, phosphorylation of SAPK/JNK was not reverted at the observed neuroprotective doses of BOS. In conclusion, we suggest a novel mechanism for the neuroprotective effect of BOS involving the inhibition of cellular PARylation. © 2021 Wiley Periodicals LLC
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    Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives
    (Bentham Science Publishers, 2022) Yilmaz, Sinem; Tok, F.; Atalay-Sahar, Esra; Koçyi?it-Kaymakçio?lu, Bedi?A; Ballarkırmızıbayrak, Petek
    Background: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of Endoplasmic Reticulum (ER) stress and subsequent activation of the Unfolded Protein Response (UPR) has been proposed as a potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. Objective: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. Methods: Cell proliferation assays were performed on HeLa, Capan-1, MCF-7, HCC-1937, and MRC-5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. Results: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of proapoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and-7. The flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). Conclusion: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways. © 2022 Bentham Science Publishers.
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    Novel regulation mechanism of adrenal cortisol and DHEA biosynthesis via the endogen ERAD inhibitor small VCP-interacting protein
    (Nature Research, 2022) İLhan, Recep; Üner, Göklem; Yilmaz, Sinem; Atalay-Sahar, Esra; Cayli, Sevil; Erzurumlu, Yalcin; Gözen, O?uz
    Endoplasmic reticulum-associated degradation (ERAD) is a well-characterized mechanism of protein quality control by removal of misfolded or unfolded proteins. The tight regulation of ERAD is critical for protein homeostasis as well as lipid metabolism. Although the mechanism is complex, all ERAD branches converge on p97/VCP, a key protein in the retrotranslocation step. The multifunctionality of p97/VCP relies on its multiple binding partners, one of which is the endogenous ERAD inhibitor, SVIP (small VCP-interacting protein). As SVIP is a promising target for the regulation of ERAD, we aimed to assess its novel physiological roles. We revealed that SVIP is highly expressed in the rat adrenal gland, especially in the cortex region, at a consistently high level during postnatal development, unlike the gradual increase in expression seen in developing nerves. Steroidogenic stimulators caused a decrease in SVIP mRNA expression and increase in SVIP protein degradation in human adrenocortical H295R cells. Interestingly, silencing of SVIP diminished cortisol secretion along with downregulation of steroidogenic enzymes and proteins involved in cholesterol uptake and cholesterol biosynthesis. A certain degree of SVIP overexpression mainly increased the biosynthesis of cortisol as well as DHEA by enhancing the expression of key steroidogenic proteins, whereas exaggerated overexpression led to apoptosis, phosphorylation of eIF2?, and diminished adrenal steroid hormone biosynthesis. In conclusion, SVIP is a novel regulator of adrenal cortisol and DHEA biosynthesis, suggesting that alterations in SVIP expression levels may be involved in the deregulation of steroidogenic stimulator signaling and abnormal adrenal hormone secretion. © 2022, The Author(s).
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    Potent telomerase activators from a novel sapogenin via biotransformation utilizing Camarosporium laburnicola, an endophytic fungus
    (BioMed Central Ltd, 2023) Küçüksolak, Melis; Yilmaz, Sinem; Ballar Kirmizibayrak, Petek; Bedir, Erdal
    Background: Cycloartane-type triterpenoids possess important biological activities, including immunostimulant, wound healing, and telomerase activation. Biotransformation is one of the derivatization strategies of natural products to improve their bioactivities. Endophytic fungi have attracted attention in biotransformation studies because of their ability to perform modifications in complex structures with a high degree of stereospecificity. Results: This study focuses on biotransformation studies on cyclocephagenol (1), a novel cycloartane-type sapogenin from Astragalus species, and its 12-hydroxy derivatives (2 and 3) to obtain new telomerase activators. Since the hTERT protein levels of cyclocephagenol (1) and its 12-hydroxy derivatives (2 and 3) on HEKn cells were found to be notable, biotransformation studies were carried out on cyclocephagenol and its 12-hydroxy derivatives using Camarosporium laburnicola, an endophytic fungus isolated from Astragalus angustifolius. Later, immunoblotting and PCR-based ELISA assay were used to screen starting compounds and biotransformation products for their effects on hTERT protein levels and telomerase activation. All compounds showed improved telomerase activation compared to the control group. Conclusions: As a result of biotransformation studies, seven new metabolites were obtained and characterized, verifying the potential of C. laburnicola as a biocatalyst. Additionally, the bioactivity results showed that this endophytic biocatalyst is unique in transforming the metabolites of its host to afford potent telomerase activators. © 2023, The Author(s).
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    Screening of cytotoxicity and DNA topoisomerase IIa inhibitory activity of Turkish Onosma species
    (Turkiye Klinikleri, 2021) Güzel, Özge; Duman, Seda; Yilmaz, Sinem; Karakoyun, Çiğdem; Kul, Demet; Pirhan, Ademi Fahri; Bedir, Erdal
    Onosma L., the largest genus of Boraginaceae, is represented by 105 species in Turkey with an endemism rate of 52%. Phytochemical studies indicate that Boraginaceae plants mainly comprise naphthoquinones with a wide range of biological activities including anticancer, antiinflammatory, wound healing, and antioxidant effects. However, few taxa of the genus Onosma have been investigated in detail for their bioactivities. Considering the high rate of endemism and an inadequate number of bioactivity screening studies in literature, we aimed to evaluate the cytotoxic effects and topoisomerase inhibitory activities of some Onosma species growing in southwestern Turkey. Here, we describe a comprehensive cytotoxic activity screening study on petroleum ether, dichloromethane, and methanol extracts of the roots of 20 identified and one unidentified Onosma taxa. The MTT cell viability assay has been performed to investigate the cytotoxicity of the extracts against seven cancer cell lines (MCF-7, HeLa, Hep G2, A549, Capan-1, HCC-1937, and DU-145) and a noncancerous cell line (MRC-5), while doxorubicin was served as a positive standard. The petroleum ether extracts of O. aksoyii Aytaç&Türkmen, O. isaurica Boiss. and Heldr., O. taurica Pallas ex Willd. var. taurica and O. alborosea Fisch. & C.A. Mey subsp. alborosea var. alborosea were determined as the most active ones based on their IC50 values. DNA topoisomerase II? inhibition assay was conducted on the petroleum ether and dichloromethane extracts of these four active species, and almost all tested extracts demonstrated strong inhibition on the enzyme at a concentration of 0.1 mg/mL. Our cytotoxicity screening results were consistent with the findings of the topoisomerase II? inhibition test. This study advocates the significant role of Onosma species in the field of anticancer drug discovery. © TÜBİTAK.
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    Telomerase activators from 20(27)-octanor-cycloastragenol via biotransformation by the fungal endophytes
    (Academic Press Inc., 2021) Duman, Seda; Ekiz Dinçman, Güner; Yilmaz, Sinem; Yusufoğlu, Hasan Soliman; Ballar Kirmizibayrak, Petek; Bedir, Erdal
    Cycloastragenol [20(R),24(S)-epoxy-3?,6?,16?,25-tetrahydroxycycloartane] (CA), the principle sapogenol of many cycloartane-type glycosides found in Astragalus genus, is currently the only natural product in the anti-aging market as telomerase activator. Here, we report biotransformation of 20(27)-octanor-cycloastragenol (1), a thermal degradation product of CA, using Astragalus species originated endophytic fungi, viz. Penicillium roseopurpureum, Alternaria eureka, Neosartorya hiratsukae and Camarosporium laburnicola. Fifteen new biotransformation products (2–16) were isolated, and their structures were established by NMR and HRESIMS. Endophytic fungi were found to be capable of performing hydroxylation, oxidation, ring cleavage-methyl migration, dehydrogenation and Baeyer-Villiger type oxidation reactions on the starting compound (1), which would be difficult to achieve by conventional synthetic methods. In addition, the ability of the metabolites to increase telomerase activation in Hekn cells was evaluated, which showed from 1.08 to 12.4-fold activation compared to the control cells treated with DMSO. Among the compounds tested, 10, 11 and 12 were found to be the most potent in terms of telomerase activation with 12.40-, 7.89- and 5.43-fold increase, respectively (at 0.1, 2 and 10 nM concentrations, respectively). © 2021 Elsevier Inc.